The overall purpose of Dr. O'Donnell's Genomic Epidemiology of Cardiovascular Disease research program during FY 2013 is to investigate the epidemiology and genetic/genomic epidemiology of subclinical and clinical atherosclerotic cardiovascular disease (CVD) and its risk factors, including hemostatic and thrombotic risk. The longer term goal is to translate these results to prediction, prevention and personalization of CVD medicine for human populations. The major projects have emanated from the SNP Health Association Resource (SHARe), the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium, and collaborative DNA and RNA sequencing projects. Dr. O'Donnell is the Associate Director of the NHLBI's Framingham Heart Study (FHS), Scientific Director and Steering Committee Chair of the NHLBI's Framingham Heart Study (FHS) SHARe Program, co-founder and Steering Committee Co-chair of the CHARGE Consortium, and Co-Director of the HeartGO Consortium of the NHLBI GO Exome Sequencing Project (ESP). Research Subjects: The research subjects consist primarily of participants of the Framingham Heart Study FHS original cohort, Offspring cohort and Generation 3, and secondarily of participants of several collaborating cohort studies. Phenotyping: Phenotyping consisted of: (a) risk factor measures from usual clinical exams (lipids, blood pressure, anthropometric and physical examination); (b) biomarkers from peripheral blood (eg, C-reactive protein, fibrinogen, von Willebrand factor, platelet aggregation, circulating bilirubin); (c) imaging measures of subclinical atherosclerosis (coronary and abdominal and thoracic aortic atherosclerosis by multidetector CT imaging (MDCT) in 3500 Offspring and Generation 3 subjects; carotid intimal medial thickness (CIMT) and carotid plaque by B-mode ultrasonography in 3800 Offspring: aortic plaque, LV mass by cardiovascular magnetic resonance imaging (CMRI) in 1800); (d) clinical CVD outcomes (myocardial infarction; coronary heart disease; CVD) adjudicated by a physician endpoint validation committee; (e) gene expression of lymphocyte- and platelet-derived RNA using rtPCR, whole genome RNA profiling (Affymetrix Exon Array), and next-generation RNA sequencing. Genotyping in SHARe and resequencing: Genotyping derived from two dense genomewide SNP scans, a 100K SNP scan (Affymetrix platform) in 1400 FHS Offspring and original cohort subjects and a 550K SNP scan (Affymetrix platform, 250K Nsp and 250K Sty and 50K gene-focussed MIP) in 9,400 FHS subjects from all three generations. Imputation of the 550K SNPs was conducted to 2.4 million HapMap SNPs using MACH and to 40 million SNPs from the 1000 Genomes Project. Additional SNP genotyping is being conducted using various platforms including 250K functional exon variants on the exome chip (Illumina). Next-Generation sequencing including targeted gene region sequencing, whole exome sequencing, and whole genome sequencing, is being conducted in several US genome centers. Statistical association and linkage methods: Statistical association analyses of genomewide association (GWA) of genotypes with phenotypes were conducted using mixed linear and/or logistic regression, generalized estimating equations, and survival analyses, when appropriate; additionally, family based association testing. Statistical linkage analyses were conducted using SOLAR. Testing for association of low frequency variants and burden of rare variants was conducted using various tests. Replication Collaboration with the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium: To seek strong evidence for replication, we combined data within a consortium of prospective, observational cohort studies with genomewide SNP scans and a large, common set of phenotypes. In silico replication meta-analysis is performed. Research Accomplishments for Major Projects Directed by Dr. O'Donnell in FY 2013: 1. Bioinformatics Databases and Tools: Our group conducted comprehensive studies of a large database we compiled of >1400 genomewide association (GWA) studies through 2012. We have used this catalogue to conduct and publish an survey of the reporting of results across GWA studies. 2. Genetic determinants of valve calcium: In conjunction with the CHARGE Consortium, we reported gene loci, including LPA gene variants, associated with aortic valve calcification and prospectively associated with aortic stenosis (published). A novel Mendelian randomization experiment was conducted to strengthen evidence for a causal association. 3. Genetic determinants of hemostatic factors and other biomarkers: The largest ever GWAS meta-analysis in the CHARGE Consortium, we reported several novel loci underlying circulating PAI-1 in a GWA meta-analysis (published) as well as over a dozen novel loci underlying circulating fibrinogen from a large multiethnic GWA meta-analysis (published). Further studies provide evidence against any significant association of these loci with myocardial infarction. 4. Genetic determinants of subclinical atherosclerosis and risk factors: In conjunction with the CHARGE Consortium, we have completed 1000Genomes imputed GWA analysis of coronary artery calcification (in preparation) and carotid IMT (in preparation). 5. Genetic determinants of myocardial infarction/coronary heart disease: We contributed to the largest meta-analysis of coronary artery disease to date, CARDIOGRAM Plus C4D, reporting over 40 total loci (published). 6. Epidemiology of the risk of subclinical disease, metabolomics and genetics: We reported the increased risk for coronary artery calcium of long-term exposure to lipid subfractions and of a lipid genetic risk score (published). In the CHARGE Consortium, we have completed a GWAS for incident MI (submitted). We are developing an updated Framingham CHD risk score that includes family history in the model (in preparation). Selected references (out of >50 publications published/in press in PubMed October 2012 to September 15 2013): 1. Sabater-Lleal M,...O'Donnell CJ. A Multi-Ethnic Meta-Analysis of Genome-Wide Association Studies in Over 100,000 Subjects Identifies 23 Fibrinogen-Associated Loci but no Strong Evidence of a Causal Association between Circulating Fibrinogen and Cardiovascular Disease. Circulation. 2013 Aug 22. Epub ahead of print 2. Thanassoulis G, Peloso GM, O'Donnell CJ. Genomic medicine for improved prediction and primordial prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2013 Sep;33(9):2049-50. 3. Rogers IS,..., O'Donnell CJ. Distribution, determinants, and normal reference values of thoracic and abdominal aortic diameters by computed tomography (from the Framingham Heart Study). Am J Cardiol. 2013 May 15;111(10):1510-6. 4. Thanassoulis G,..., O'Donnell CJ, Post WS; CHARGE Extracoronary Calcium Working Group. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013 Feb 7;368(6):503-12. 5. CARDIoGRAMplusC4D Consortium, Deloukas P, ..., O'Donnell C,...,Samani NJ. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet. 2013 Jan;45(1):25-33. 6. Tsao CW, ..., O'Donnell CJ. Relations of long-term and contemporary lipid levels and lipid genetic risk scores with coronary artery calcium in the framingham heart study. J Am Coll Cardiol. 2012 Dec 11;60(23):2364-71. 7. Huang J, Sabater-Lleal M, ..., O'Donnell CJ, Hamsten A. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood. 2012 Dec 6;120(24):4873-81.